Study On The Pilot-scale Synthesis Of Novel SGLT2Inhibitor Tianagliflozin

Diabetes is a common endocrine and metabolic disease, which is caused by the interaction of genetic and environmental factors. It is due to absolute lack of insulin or relative lack of insulin, which lead a group of metabolic diseases characterized by disorders of carbohydrate metabolism even fat and protein metabolism. Every year, there are a large number of patients around the world die from diabetes and its complication. By2025, the global number of diabetes will increase to380million, or7.9%of the total adult population, and it will rise to438million by2030. And it will do harm to human health.Although there are a variety of anti-diabetic drugs available, the hyperglycemia still can’t be controlled even accompanied by side effects. Therefore new agents with novel mechanisms of action are urgently needed. In recent years, researchers have discovered a new mechanism of glycemic control that inhibition of SGLT2is able to suppress the reabsorption of glucose from glomerular filtrate into blood, which will lower the blood glucose levels. Many experimental data of animal and human show that it is an effective and innovative method in lowering plasma glucose of type2diabetic patients by inhibiting the active of SGLT2, so SGLT2inhibitors become a new target of anti-diabetic drugs. Currently, there are five categories SGLT2inhibitors under development, including O-aryl inhibitor, C-aryl inhibitor C, O-Spiro inhibitors, N-aryl-inhibitor and non-sugar inhibitors. C-aryl inhibitor has been widely studied for its good hypoglycemic activity, and it also can resist the degradation by β-glycosidase. And the most advanced one, dapagliflozin has been approved recently in EU.In the earlier work of our Group, we discovered that deoxygenation of the6-OH in the sugar moiety of dapagliflozin led to a more potent SGLT2inhibitory activity. In in vitro assay,6-deoxydapagliflozin is a more active SGLT2inhibitor with IC50=0.67nM against hSGLT2(human SGLT2) as compared with1.1nM for dapagliflozin, making it one of the most active SGLT2inhibitor discovered so far in this field. It could also introduce more urinary glucose in rat urinary glucose excretion test (UGE) and exhibited more potent blood glucose inhibitory activity in rat oral glucose tolerance test (OGTT) than dapagliflozin.Based on these finding, we first carried out the retro synthetic analysis of6-deoxydapagliflozin, followed by designing a new synthetic route. After optimizing the reaction conditions, we finally got the optimized reagents and reaction condition, which were suitable for pilot-scale synthesis of the target molecule. Finally, the polymorphism of6-deoxydapagliflozin was also studied.